The human immunodeficiency virus (HIV) both relies on host cell proteins for its replication, and is opposed by host cell factors, called "restriction factors" with the potential to significantly control viral replication. Our hypothesis is that humans are so susceptible to HIV because our antiviral genes are poorly adapted to this virus, and because HIV-1 has adapted to humans by its own evolution of specific antagonists to these antiviral genes. While some restriction factors are very active against HIV, others work poorly in humans or are polymorphic in the human population with both active and inactive versions. In the APOBEC3 locus of restriction factors, APOBEC3H stands out because some humans make active versions of this protein, while others do not. We will determine how important APOBEC3H is for HIV infection by determining whether or not HIV adapts in humans who encode the most active form of APOBEC3H. We will also study the evolution and function of APOBEC3DE which is a restriction factor that has rapidly evolved since the human-chimpanzee divergence, and we will the exploit the natural infection of African Green Monkeys (AGMs) subspecies with divergent SIVs to understand how polymorphism in the APOBEC3 locus affects the evolution of the lentivirus-host relationship. Finally, we will characterize a restriction factor against HIV, called Viperin, that acts at a late stage of virus replication by a novel mechanism. Overall, the goal of this proposal is to understand how the past evolution and function of these restriction factors impacts HIV replication in humans. PUBLIC HEALTH RELEVANCE: The human immunodeficiency virus (HIV) is the major viral pandemic of the past 25 years. Our study will elucidate the human defenses to HIV in order to understand why humans are so susceptible to this virus, how HIV evades our defenses, and how previous infections of human ancestors may have shaped the evolution of our viral defenses to HIV.